Phenyl alkyl-1, 2 dicarbamates



' May29, 1959, now'Patent .No. 3,066,164.

3,265,127 PHENYL ALKYL-1,2 DICARBAMATES Charles D. Bossinger, Kankakee,and Kelley G. Taylor,

Decatur, Ill., assignors to Armour Pharmaceutical Company, Chicago,Ill., a corporation ofDelaware No Drawing. Filed June 26, 1962, Ser. No.205,199

' 3 Claims. (Cl. 260-482) and to a method of treating thecentra'lnervous system by administering these compounds. "The novel com-3,265,727 Patented August 9, 1966 ICC mate by reaction with phosgene andammonolysis. For example, the carbonyl chloride derivative can bereacted with diethyl aniline, and then with concentrated ampounds ofthis invention can be classifiedlgenerally as phenyl alkyldicar'bamates. V v v It is an object of this invention toprovidecarbamate compounds for usein treating the central system. Morespecifically, it is an object toprovide carbamate compoundswhichexhibitspecial and distinctive properties, or

tral nervous system. For example, it is an object to provide carbamatecompounds which function lprimarily as muscle relaxants, and whichexhibit relatively little sedative efiect. Further objects andadvantages will be indicated in the fol-lowing detailed specification.

The pheny-l alkyl dicarbamate conipounds which are useful in thetreatment of the centralncrvoussystem in accordance with the presentinvention'are characterized by the following structural formulas In theforegoing formula, R is either hydrogen or an alkyl group containingfrom 1 to 3 carbon'atoms, R is either hydrogen or an alkyl .groupcontaining from 1 to 3 carbon atoms; and R and R are either hydrogen ormethyl. For one preferred sub-class of compounds R is hydrogen, R ishydrogen or-an alkyl group containing from i to 3 carbon atoms, and Rand R are hydrogen.

Examples of such preferred compounds are lgphenyl ethyl-1,2dicarbamate,l-phenyl propyl-l, 2-dicarbamate and l-phenyl butyl'-l,2dicarbama'te.Other compounds coming within the scope of the present invention are 2-phenyl propyI-LZ-dicarbamate, 2 -phenyl butyl-l,2-dicar-' bamate,2-phenyl butyl-2-,3-dicarbamate, 2-phenyl pentyl- 2,3 dicarbamate and3-phenyl pentyI-ZJ-dicarbamate.

The foregoing dicarba-mate compoundscan be prepared readily from thecorresponding monocarbama-te' compounds. For example, l phenylethyl-l,2-dica' rbamate can be prepared from 2-hydroxy-2-phenyl ethylcatbamate. Theintermediatemonocarbamate will contain a hydroxylcombinations of properties in thetreatment of the cenof 1 hour,whereafter 48.0 gms. of diethylaniline in 100 l ml. of benzene was addedand the mixture stirred for an group bonded to the same carbon atom asthe phenyl group. Such.monocarbamates can be prepared by the processdescribed in application Serial No. 816,700, filed Inthe procedure ofthis application, a 1,2-glycol is converted to thecorresponding-carbonate, 'and the carbonate is subjected to ammonolysisto obtain the desired carbamate.

Preferably, 1,2-gl ycol is condensed with a halo-formic ester to obtainan acyclic carbonate which is then subjected to ammonolysis to obtainthe monocairbamate. The intermediatemonocarba-mate can be converted tothe dicarbacrystals were separated from the mother liquor. Crystalmoniumhydroxide. ,Since the particular process for preparing the dicarbamatecompounds does not form a part of the present invention, it is notbelieved it will be necessary to further describe such processes herein,except as illustrated by the following examples.

In utilizing the compounds of this invention for central nervous systemtreatment and particularly to promote muscle relaxation, it is preferredto administer the compounds orally. Since the compounds arewell-absorbed the pharmaceutical carrier as the dicarbamate compound.

Various edible pharmaceutical carriers,. or mixtures thereof can beused. For example, a mixture of lactose, dibasic,calcium phosphate, andcornstarch is'suitable. Additional ingredients can be included, such aslubricants like magnesium stearnte.

When administering the compounds of this, invention orally for centralnervous system treatment, the total daily dose will usually fall withinthe range from 400 to 2,000 milligrams of the dicarbamate compound per24 hour period. Typically, the daily dose will range from 600 to 1,600milligrams. In some cases, it may sometimes be desirable to administeras much as 2,400 milligrams per day. In practicing the method of thisinvention, it will therefore be convenient to have the dicarbamatecompound combined with a pharmaceutical carrier, such as lactose, andprepared in tablets or other dosage unit form. Each tablet or dosageunit can contain from 50 to 600 milligrams of the d-icarbamate compound.For example, tablets containing 200 milligrams of the dica-rbamatecompound can be administered either 1 tablet three times a day toachieve a daily dose of 600 milligrams or up to 2 tablets four times aday to achieve a daily dose of EXAMPLE 1 The following method wasutilized in preparing 2- hydroxy-Z-phenyl ethyl carbamate:

A solution of 32.0 gms. (0.3 mole) of phosgene in 200 ml. of benzene wasadded dropwise to a stirred solution of 44.2 gms. of styrene glycol (0.3mole) in 400 ml. of benzene. The solutions were maintained at atemperature of 30 C. during the addition.

. The resulting reaction mixture was stirred for a period additionalhour. About 500ml. of ice water was then added to the flask, and thebenzene layer thereupon formed separated from the aqueous layer andwashed with an additional 500 ml. of ice water.

To the benzene-soluble fraction was added 500 ml. of a 30%aqueous'ammonium hydroxide solution, and thereafter the resultingmixture was maintained at a temperature of 5 C. for a'period of 3 hours.Upon standing, needle-shaped crystals were formed, and such lization.can be facilitated by the removal of excess ammonia from thecrystallization mixture underreduced pressure. The yield of crystals was30 gms. An additional amount of reaction product was recovered fromEXAMPLE 2 The following method was utilized in the preparation ofl-phenyl ethyl-1,2-dicarbamate from 2-hydroxy-2- phenyl ethyl carbamateprepared as described in Example 1.

A solution of 32.0 gms. (0.3 mole) of phosgene in 200 ml. of benzene wasadded dropwise to a stirred solution of 54.3 gms. of 2-hydroxy-2-phenylethyl carbamate (0.3 mole) in 400 m1. of benzene. The solutions weremaintained at a temperature of 30 C. during the.

addition.

The resulting reaction mixture w'as stirred for a period of 1 hour,whereafter 48.0 gins. of diethyla'niline in 100 ml. of benzene was addedand the mixture stirred-for an additional hour. About 500 ml:-oficewater was then added to the fiask, and the benzene-.la'=ye'rlf-t'hereupoh formed separated from the aqueous layer andwashed with an additional 500 ml. of ice water.

To the washed benzene layer was added 500 ml. of. a I

30% aqueous ammonium hydroxide solution, and thereafter the resultingmixture was maintained at a tempera- Lure of 5 C. for a period of 3hours. The white precipitate thereupon formed was separated from themother liquor and'recrystallized from chloroform containing a minorportion of acetone. The yield of crystalline product was gms. having amelting point of This reaction product was subjected to analysis and theresults were as follows.

Calculated: C, 53.57; H, 5.36; N, 12.5. Analyzed: C, 53.59, 53.40; .H,5.56, 5.41; N, 12.54, 12.40.

EXAMPLE 3 l-phenyl-l,2-propanediol, 15.2 g. (0.1 mole) was dissolved inml. of pyridine dried over NaOH. To this chilled solution with stirringwas added, dropwise, 19.3 g. (0.11 mole) of phenyl chlorocarbonate inhalf an hour. Stirring was continued at room temperature for anothertwii' hours. Ether, 100 ml., and then ice cold water, ml. were added.The ether layer was separated, washed with 50 ml. of cold hydrochloricacid twice, 50 ml. cold water once, 50 ml. of cold 10% NaHCO twice, 50ml, cold water once, and dried over anhydrous .CaCl The dried ethersolution was poured into EXAMPLE 4 To a stirred solution of 176.6 g ofstyrene glycol (1.28 mole) in 2400 ml. of benzene was added, dropwise, asolution of 128 g. of phosgene (1.2 mole) in 800 ml. of benzene. Thetemperature was maintained at 30 C. After the addition was completed,the reaction mixture was stirred for another hour. Diethylaniline 1.92g. in 200 ml. of benzene was then added. After an additional hour ofstirring, 2 liters of water was added. The benzene y r was s parated andwashed with water.

One fourth of this benzene solution which contained approximately 0.3mole of the chlorocarbonate was placed in a three-ncckcd flask. fittedwith a mechanical stirrer, an addition "funnel, and a condenser. Whilestirring at ice-hath temperature, 501) ml. of 40 percent dintcthylaminewas added. Stirring was continued for two hours. The reaction mixturewas allowed to warm up to room temperature overnight.

Thebcnzene layer was separated and evaporated under reduced pressure.The residual brown oil was distilled twice under reduced pressure togive an oil, 42 g. 8.1. l30/l50 mg. yield 66 percent.

To a stirred solution of 21 g. of this oil in 200 ml. of benzene wasadded, gradually 15 g. of phosgene in ml. of benzene. After thirtyminutes, diethylaniline 19 g. was added slowly. Stirring was continuedfortwo and one-half to three hours at room temperature. The re actionmixture was then cooled to 5 C. After it was washed with ice water, 170ml. of 30 percent NH,OH was added. The reaction mixture wasstirred at 5C. for one and one-half hours and left standing overnight atroomiterjnperature. tit-The aqueous layer was separated. 'Ammonia was removed'underreduced pressure without applying external "heat"; Asolid,"12.7 g. was isolated by filtration. After drying in a vacuumdesiccator over CaCl; for twenty-four hours, the solid melted at 143-145C. It was recrystallized from benzene and petroleum ether (2040' C.) togive crystals, 11.7 g. of 2-(N,N-dimcthyl carbamyloxy)-1- phenylethylcarbamate M.P. 149150 C.

EXAMPLE 5 Tablets for oral administration were prepared from 1 phenylethyl 1,2 dicarbamate. This compound was combined with a mixedpharmaceutical carrier in the ratio of 2 parts by weight of thedicarbamate compound per 3 parts of the pharmaceutical carrier. Themixed carrier contained dibasic calcium phosphate as the principalingredient together with smaller amounts of lactose and 1 part ofcornstarch. A small amount of magnesium stcarate was also included.

The dicarbamate compound, the calcium phosphate, the lactose, and partof the magnesium stearate were blended and dry mixed until a uniformcomposition was obtained. This was formed into firm slugs no greaterthan V4 inch thick. The slugs were then put through an oscil latinggranulator equipped with a 10 mesh screen. The cornstarch and a littlemore magnesium stearate was added at intervals while the slugs werebeing sized. The granulation was blended in a drum tumbler for 30minutes. Following this, the granulation was compressed into tablets of500 mg. per tablets containing 200 milligrams of the carbamate compound.

While in the foregoing specification this invention has been describedin relation to certain preferred embodiments, and many details have beenset forth for purpose of illustration, it will be apparent to thoseskilled in the art that the invention is susceptible to additionalembodiments, and that certain of the details set forth herein can bevaried considerably without departing from the basic principles of theinvention.

We claim:.

1. Phenyl alkyl dicarbamate compounds characterized by the structuralformula wherein R is selected from the class consisting of hydrogen, andan'alkyl group containing 1 to 3 carbon atoms and R and R are selectedfrom the class consisting of hydrogen and methyl.

2. The compound t-phenyl ethyl-1,2-dicarbamate.

7 6 3. The compound 2-(N,N-dimethyl carbarnyloxy)-1- 2,978,489 4/1961Frankel 260-482 phenylethyl carbamate. 3,036,954 5/1962 Robbins167----65 References Cited by the Examiner FOREIGN PATENTS UNITED STATESPATENTS 5 218,080 7/1957 Australia.

2,627,524 2/1953 Malkemue 260-482 LORRAINE A. WEINBERGER, PrimaryExaminer.

2,890,984 6/1959 Sahyun 167-65 Primary Examiners 2,934,559 4/1960Beinfest 260-482 1 2,967,880 1/1961 Finke et a1 260-482 10 SABATINE, P-CLARKE, HALLUIN.

' Assistanl Examiners.

1. PHENYL ALKYL DICARBAMATE COMPOUNDS CHARACTERIZED BY THE STRUCTURALFORMULA